Compartmentation And Inborn Errors Of Metabolism Notes

COMPARTMENTATION AND INBORN ERRORS OF METABOLISM

Overview: major pathways of metabolism

Compartmentation

Advantage:

-clustering of related functions, allows enzymes to work in a favoured common environment

-Through isolation, accesss of substrates into the compartments can be controlled allowing for regulation

-It also removes potentially harmful processes from general cell environment

Disadvantage

-Isolation means that transport mechanisms are needed for substrates and products.and intrinsic components of the compartment

1) CTYOPLASM AND CELL MEMBRANE

-Cell membrane: uptake of substrates- carriers/pumps, determines the permeability of the cell to solutes

-cytoplasm: storage = Glycogen, triglyceride

-cytoplasm = activation for oxidation

-glucose glucose-6-P

-fatty acids fatty acyl coA

-signal transduction: integration of metabolism between different organs, hormones binding controls metabolism

-protein synthesis

2) MITACHONDRIA

a) clustering of major energy forming reactions

-B oxidation of fatty acids

-pyruvate oxidation

-oxidation of amino acids

-urea formation (liver)

b) Generation of key metabolic intermediates and reduced cofactors

-acetyl CoA

-TCA cycle intermediates

-NADH, FADH2 (reducing power for biosynthesis)

c) Final common pathway of chemical energy production (ATP)

-TCA cycle

-ETC , oxidative phosphorylation

-ATP synthase

-ATP/ADP translocation

Mitachondrial isolation: SUBSTRATES and PRODUCTS

Outer membrane: has transmembrane channels that are freely permeable to molecules of up to a molecular weight of 10000. Based on the porin protein

Inner membrane has a high selective permeability:

-There are specific carriers for pyruvate, some amino acids, ADP/ATP, Pi, citrate, malate, alpha ketoglutarate

-There are NO mechanisms for transporting NADH, acetyl coA, fatty acyl coA, so there are specific shuttle systems for transporting these molecules.

-Shuttle systems: NADH (malate-aspartate shunt), acetyl coA (transported out as citrate), fatty acyl coA (transported via the carnitine esters). Through having shunt systems it allows regulation of entry and exit of these molecules.

Mitachondrial isolation: genetic and proteins

Mitochondrial protein components

-almost from nuclear genes synthesised in the cytoplasm taken up in the mitochondria according to N terminal leader sequence

Uptake of protein into the mitachonrdria- inner membrane receptor, that transports the proteins into the matrix using the proton gradient

Within the matrix of the mitochondrion- the import sequence is removed and the proteins are folded and assmbeld with chaperon proteins.

Mitachondrial Genome

-16500 basepairs of circular DNA (like bacteria)

-maternally transmitted

-up to 10000 copies per cell

Codes for: 13 subunits of the electron transport chain complexes and ATP synthase

-set of 22 tRNAs

-set of ribosomal RNAs

-has its own genetic code- few codons are different, this is seen as transplanting mitochondria mRNA into the cytoplasm doesn’t generate the same functional protein

-in conjunction with nuclear derived proteins mitochondria can replicate: DNA replication, transcription/processing of MRNAs , translation of gene products . Mitachondrial density can vary both up and down – there can be a ten fold increase in mitochondria in resting skeletal muscle if it is repeatedly stimulated to contract over a long period of time. Density also increases during hypoxia.

-Evolutionary origin of mitochondria suggests that they may have originally been free living bacteria that became incoroporated in a symbiotic relationship ‘symbionts’

Mitachondrial disease:

Leber hereditary optic neuropathy – causes blindness – mutation in the DNA for NADH-Q reductase (complex 1)

Myoclonic epilepsy with ragged red fibres

-symptoms: Ragged red fibres- clumps of diseased mitochondria accumalte in the subscarcolemmal region of the muscle fibre and appear as ragged red fibres . There is also short stature, hearing loss, intolerance to excercise

-it is caused by maternally inherited mutation in mitochondrial DNA and disrupts the proteins that are needed for oxidative phosphorylation.

MELAS neuropathology

-muscle weakness, headache

-there is a build up of lactic acid in the body – increased acidity leads to vomiting, abdominal pain,

-stroke like episodes

-due to mutations in the mitochondrial DNA

Mutations in nuclear genes : Mitachondrial DNA polymerase can lead to different deletions in the mitochondrial proteins / reduced copy number

ENDOPLASMIC RETICULUM-GOLGI APPARATUS-SECRETORY VESICLE SYSTEM

Endoplasmic reticulum

Biosynthesis of lipids

Phospholipid synthesis occurs in the cytosol adjacent to the ER membrane.

-Glyecerol-3-Phosphate binds to 2 fatty acids to form phoshptidate which is then converted into phospholipid.

-the final product is flipped over to the other side if necessary by specific protein

- A vesicle then buds of from the ER containing phoshpolipids destined for cytoplasmic cellular membrane. Glycolipids- sugar residues are added in the golgi apparatus.

Synthesis of complex carbohydrates

Dolichol phosphate- specialised lipid molecule located in the ER membrane.

Terminal phosphate group of dolichol phosphate is the site of attachment of activated oligosaccharide

-The activated oligosaccharide which is attached to the dolichol phosphate is transferred a specific arginine residue of a growing polypeptide chain

-the activated sugar and the enzyme that transfers the oligosaccharide to the protein are located on the luminal side of the ER

-protein in the lumen of the ER are then transported to the golgi for further modification

Synthesis of glycoproteins

-N linked glycosylation occurs in the lumen of the ER but O linked glycosylation occurs in the golgi complex.

Smooth ER

-Smooth ER contains cytochrome P450 class of enzymes

– these detoxifies both endogenous and exogenous compounds

-they are also involved in the synthesis of steroids

- Smooth ER also elongates fatty acids over C16 during biosynthesis of lipids

-Final...

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